Lymphocytes are one of several populations of white blood cells; they specifically recognize and respond to foreign antigen. The three major classes of lymphocytes are B lymphocytes (B cells), T lymphocytes (T cells) and natural killer (NK) cells. B lymphocytes are the cells responsible for antibody production and provide humoral immunity. B cells mature within the bone marrow and leave the marrow expressing an antigen-binding antibody on their cell surface. When a naive B cell first encounters the antigen for which its membrane-bound antibody is specific, the cell begins to divide rapidly and its progeny differentiate into memory B cells and effector cells called plasma cells. Memory B cells have a longer life span and continue to express membrane-bound antibody with the same specificity as the original parent cell. Plasma cells do not produce membrane-bound antibody but instead produce secreted form of the antibody. Secreted antibodies are the major effector molecules of humoral immunity.
A group of tumor necrosis factor (TNF) receptors found on the surface of B cells under various conditions are among the cellular regulators of B cell function in the immune system. In particular, three TNF receptors: transmembrane activator and CAML interactor (TACI), B cell activator belonging to the TNF family receptor (BAFF-R), and B cell maturation protein (BCMA) are known to bind one or both TNF ligands-Lymphocyte stimulator (BLyS also known as BAFF, TALL-1, ztnf4 and THANK) and a proliferation-inducing ligand (APRIL). Specifically, TACI and BCMA are known to bind both BLyS and APRIL and BAFF-R binds only BLyS.
A number of BLyS and/or APRIL antagonists have been developed in order to block the various functions of BLyS, which include but should not be limited to B cell co-stimulation, plasmablast and plasma cell survival, Ig class switching, enhanced B-cell antigen presenting cell function, survival of malignant B cells, development of B-1 cell function, B cell development beyond the T-1 stage, and complete germinal centre formation Some of these molecules can also bind to and block the effect of APRIL on B cells and other components of the immune system (Dillon et al. (2006) Nat. Rev. Drug Dis. 5, 235-246). Molecules that have been developed to affect B cell function by interfering with BLyS and/or APRIL binding include BLyS antibodies such as Lymphostat-B (Belimumab) (Baker et al, (2003) Arthritis Rheum, 48, 3253-3265 and WO 02/02641); receptor-extracellular domain/Fc domain fusions proteins such as TACI-Ig, including one particular embodiment, atacicept (U.S. Patent Application No. 20060034852), BAFF-R-Fc (WO 05/0000351), and BCMA-Ig or other fusion proteins utilizing receptor extracellular domains. A further class of BLyS and/or APRIL antagonists include other molecules relying on BLyS binding ability to block binding to its receptors such as AMG 623, receptor antibodies, and other molecules disclosed in WO 03/035846 and WO 02/16312
The current approach for the treatment of autoimmune diseases is suppression of the unwanted immune reaction. For example, in the treatment of lupus nephritis (LN), a serious complication involving the kidney of patients suffering from systemic lupus nephritis (SLE), several immunosuppressive drugs have proven beneficial. These drugs include cyclophosphamide (CYC), azathioprine (AZA), cyclosporine A (CSA), and mycophenolate mofetil (MMF) (for general reviews see, Mok et al. (2003) Ann Rheum Dis 62, 799-804 and Iaccarino et al. (2007) Autoimmunity Reviews 6, 190-195). Although these drugs are beneficial, there remains a need in the art to improve the response to immune suppressive drugs in order to effectively treat autoimmune disease.